Transcriptional silencing in damaged retinal ganglia

描述：（申请人的摘要）视网膜神经节细胞在各种不同的细胞中死亡。 视神经疾病，其中最普遍的是青光眼。的机理 细胞死亡是一个基因控制的程序，有4个不同的阶段。这些 阶段是（i）基因表达的早期变化，包括两个阶段， 基因的上调和下调，（ii）关键调控因子的激活， 蛋白质如p53和BAX，（iii）线粒体功能障碍，和（iv） 半胱天冬酶蛋白酶和核酸酶的活化。一个目标是发展一个 神经节细胞的神经保护策略是阻断一个或多个这些 细胞死亡的阶段。目前的尝试表明， 事件（ii-iv）不是完全神经保护性的。因此，我们建议 来表征和阻断基因表达的早期变化，特别是 下调这些细胞中的基因。初步研究表明， 神经节细胞表现出广泛的所有正常表达的减少， 在进入细胞死亡途径之前的活性基因。这包括 可以增强细胞存活的基因，包括Bc 1X和TrkB受体 基因.我们将进一步描述3类基因，这些基因可能受到 研究组蛋白去乙酰化是否是 现象的根本。这些实验将由以下人员进行： 监测神经节细胞标记基因上组蛋白的乙酰化状态 Thy 1，并通过评估组蛋白脱乙酰酶抑制剂对 Thy 1转录和下游事件的激活在细胞凋亡中的作用 神经节细胞的程序。

DESCRIPTION: (Applicant's Abstract) Retinal ganglion cells die in a variety of optic nerve diseases, the most prevalent of which is glaucoma. The mechanism of cell death is a genetically controlled program with 4 distinct stages. These stages are (i) early changes in gene expression that includes both the upregulation and downregulation of genes, (ii) the activation of key regulatory proteins such as p53 and BAX, (iii) dysfunction of mitochondria, and (iv) the activation of caspase proteases and nucleases. A goal in developing a neuroprotective strategy for ganglion cells is to block one or more of these stages of cell death. Current attempts to do this have shown that blocking late events (ii-iv) is not completely neuroprotective. As a consequence, we propose to characterize and block the early change in gene expression, specifically the downregulation. of genes in these cells. Preliminary studies indicate that ganglion cells exhibit extensive decreases in the expression of all normally active genes prior to the commitment to the cell death pathway. This includes genes that could enhance cell survival including Bc1X and the TrkB receptor genes. We will characterize further 3 classes of genes that may be affected by this silencing event and examine if histone deacetylation is the mechanism underlying the phenomenon. These latter experiments will be conducted by monitoring the acetylated status of histones on the ganglion cell marker gene Thy1, and by assessing the effects of inhibitors of histone deacetylases on Thy1 transcription and the activation of downstream events in the apoptotic program of ganglion cells.